Luteinizing Hormone Releasing Hormone, known as LHRH or GnRH, is a decapeptide that is produced in the hypothalamus and binds to a receptor on the pituitary gland causing the release of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) from the pituitary. Subsequently, LH and FSH act on the gonads to stimulate the synthesis of steroid sex hormones. The pulsatile release of LHRH, and thereby the release of LH and FSH, controls the reproductive cycle in domestic animals and humans.
Acute doses of LHRH agonists increase the levels of LH and steroid sex hormones in both animals and humans. Paradoxically, chronic doses of these agonists suppress the levels of LH and steroid hormones resulting in an inhibition of the pituitary-gonadal axis characterized by a decrease of the levels of sex steroids and the atrophy of accessory sex organs. The same effect is observed in both animals and humans after administration of acute or chronic doses of LHRH antagonists. LHRH agonists are currently used, or are under clinical investigation, for the treatment of several hormone dependent diseases such as prostate cancer, prostatic hypertrophy, endometriosis, uterine fibroids, precocious puberty, and breast cancer. They also have been used as contraceptives. For a review of LHRH analogs see J. Sandow, et al., "Hypothalamic Hormones, Chemistry, Physiology, and Clinical Applications", edited by D. Gupta and W. Voeters, p. 307 (1978).
The discovery of gonadal steroid suppression produced by an LHRH agonist led to the successful development of clinical therapeutic agents such as leuprolide, U.S. Pat. No. 4,005,063, for use in the treatment of hormone-dependent breast and prostate cancer. However, to produce an agonistic response through a receptor-substrate complex, the molecule must meet the geometrical constraints of the receptor pocket and also meet the electronic requirements of the environment. This is particularly true where the substrate happens to be a long-chain polypeptide molecule. Many LHRH agonists have been made, but no agonist of less than eight amino acids in length has shown appreciable potency. Further, these agonist compounds are not appropriate for oral administration because they lack oral activity. For example, leuprolide is less than 1% bioavailable from the duodenum. Further, the mechanism by which these agonists induce the pituitary to release large amounts of LH during the first few weeks of the desensitization period also produces undesirable side effects, which include nausea, diarrhea, hot flashes, bone pain, urinary tract obstruction, and in some cases neurological problems. Manni, et al., Endocrine Rev., 7, 89-94 (1986).
An LHRH antagonist would avoid the unpleasant side effects accompanying the initial surge of LH which follows the administration of an LHRH agonist. Therefore, it is desirable to prepare an LHRH antagonist which will suppress steroid production by blocking LH-release. LHRH agonists work through a desensitization mechanism, while LHRH antagonists block the LHRH receptor by a competitive binding mechanism.
LHRH analogs have been shown to be effective by intravenous, subcutaneous or depot administration. Intranasal and intravaginal administration are effective only at very high doses. Currently known LHRH antagonists are not orally active, showing 0.1% to 1% potency following oral administration when compared to intravenous doses, and are effective only at very high doses. This very low oral activity is due to the fact that the long peptide chain of an antagonist is readily metabolized by the enzymes that are present in the digestive system. It would, therefore, be desirable to prepare an antagonist that is stable against enzymatic degradation and that is active after oral administration in animals and humans.
The prior art includes the antifungal drug, ketoconazole, U.S. Pat. No. 4,335,125, which was found to inhibit testicular and adrenal steroid synthesis by blocking a variety of enzyme systems. See Pont, et al., Arch. Intern. Med., 142, 2137-2140 (1982); Pont, et al., Ann. Intern. Med., 97, 370-372 (1982); Pont. et al., Clin. Res., 31, 91(abstr.) (1983); Pont. et al., Clin. Res., 30, 99(abstr.) (1982); Trachtenberg, et al., J. Urol., 130, 152-153 (1983). When given orally to patients in high dosages, from 200 to 1200 mg daily, ketoconazole was found to produce a dose dependent suppression of serum testosterone. See Trachtenberg, et al., The Lancet. 2, 433-435 (1984).
It is an object of the present invention to provide a novel series of antagonists which will suppress steroid production by blocking LH-release.
It would be desirable to prepare a novel series of orally active LHRH antagonists that are stable against enzymes and are applicable to oral administration in mammals, including humans.